The major objective is to investigate the metabolism of porcine low density lipoproteins (LDL) and high density lipoproteins (HDL) in porcine hepatocytes. The pig was chosen as the experimental animal because of the similarity to humans in the distribution and composition of LDL ahd HDL and in the metabolism of these lipoproteins. Primary monolayer cultures of porcine hepatocytes have been established which synthesize glucose, albumin and VLDL apoprotein(s). LDL and HDL bind in a saturable manner and are degraded and LDL inhibits the synthesis of cholesterol. The specific aims are to: 1. characterize further the binding of LDL and HDL and study the role of the apoproteins (apoB, apoE, apoA-I) and the phospholipids in binding. 2. investigate the rate of uptake of (125I)-apoproteins and (3H)-cholesteryl esters of LDL and HDL and determine if proteolysis of the apoproteins and hydrolysis of the cholesteryl esters requires lysosomal function. 3. study the effects of LDL and HDL on cholesterol and lipoprotein metabolism; specifically, on cholesterol biosynthesis, the activities of hydroxymethylglutaryl (HMG) CoA reductase and cholesterol 7Alpha hydroxylase, and on lipoprotein biosynthesis. We will examine whether alterations in the cellular content of cholesterol affect the binding of LDL abd HDL. The major hypothesis is that porcine LDL and HDL bind to specific sites, are taken up and degraded, and then inhibit cholesterol synthesis but stimulate cholesterol 7alpha hydroxylase and apoprotein synthesis in porcine hepatocytes. An understanding of the biochemical mechanism(s) involved in the regulation of hepatic lipid, lipoprotein and bile acid metabolism may improve our knowledge of normal physiological processes and of the pathogenesis of atherosclerosis.